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CSL Behring

Beriplast P Combi-Set

1. NAME OF THE MEDICINAL PRODUCT

Beriplast P Combi-Set 0.5 ml, 1 ml, 3 ml


Powders and solvents for sealant.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Qualitative composition

Combi-Set I:
Active substances
Human fibrinogen, Coagulation Factor XIII (human), Aprotinin (bovine)
Combi-Set II:
Active substances
Human thrombin, Calcium Chloride

Quantitative composition

Combi-Set I per 1 ml
Vial 1 Fibrinogen Concentrate:
total dried substance 174 mg
fibrinogen (human plasma protein fraction) 90 mg
coagulation factor XIII (human plasma protein fraction) 60 IU
Vial 2 Aprotinin Solution:
volume 1.0 ml
bovine lung aprotinin 1000 KIU*
corresponding to 0.56 PEU**
* KIU = Kallikrein Inactivator Unit
** PEU = Ph. Eur. Unit (1 PEU ^ 1800 KIU)

Combi-Set II per 1 ml
Vial 3 Thrombin:
total dried substance 7.6 mg
with a human plasma protein fraction thrombin activity 500 IU
Vial 4 Calcium Chloride Solution:
volume 1.0 ml
calcium chloride dihydrate 5.9 mg

For the full list of excipients, see section 6.1.


CSL Behring
Beriplast P Combi-Set

3. PHARMACEUTICAL FORM

Powders and solvents for sealant.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Supportive treatment where standard surgical techniques are insufficient


 for improvement of haemostasis (including endoscopic treatment of bleeding
gastroduodenal ulcer)
 as a tissue glue to promote adhesion/sealing or as suture support

4.2 Posology and method of administration

The use of Beriplast is restricted to experienced physicians and/or surgeons.

Posology
The volume of Beriplast to be applied and the frequency of application should always be
oriented towards the underlying clinical needs of the patient.

The dose to be applied is governed by variables including, but not limited to, the type of
surgical intervention, the size of the area and the mode of intended application, and the
number of applications.

Application of the product must be individualised by the treating physician. In clinical trials,
the individual dosages have typically ranged from 0.5 to 4 ml. For some procedures (e.g.,
liver traumata, or the sealing of large burned surfaces) larger volumes (10 ml or more) may
be required.

The initial volume of the product to be applied at a chosen anatomic site or target surface
area should be sufficient to entirely cover the intended application area. The application can
be repeated, if necessary.

Paediatric population

The safety and efficacy of Beriplast in children and adolescents has not yet been established
in controlled clinical studies.
CSL Behring
Beriplast P Combi-Set

Method of administration
For epilesional use.
For instructions on reconstitution of the medicinal product before administration, see section
6.6.
The reconstituted solutions (of vial 1 and 3) are to be administered locally to the tissue
(sequentially or in combination). Unlike other haemostatic agents that must be removed
once haemostasis is achieved, Beriplast remains in place after application and is degraded
by the normal physiological process of clot lysis.
Prior to applying Beriplast the surface area of the wound needs to be dried by standard
techniques (e.g. intermittent application of compresses, swabs, use of suction devices).
Beriplast should only be reconstituted and administered according to the instructions and
with the devices as provided with this product. See section 6.6 for more detailed
instructions.

4.3 Contraindications

Beriplast must not be applied intravascularly.


Arterial and strong venous bleeding.
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

For epilesional use only. Do not apply intravascularly.

Life threatening thromboembolic complications may occur if the preparation is


unintentionally applied intravascularly.

Before administration of Beriplast care is to be taken that parts of the body outside the
desired application area are sufficiently protected (covered) to prevent tissue adhesion at
undesired sites.

As with any protein product, allergic type hypersensitivity reactions are possible. Signs of
hypersensitivity reactions include hives, generalised urticaria, tightness of the chest,
wheezing, hypotension, and anaphylaxis. If these symptoms occur, the administration has to
be discontinued immediately.

Beriplast contains bovine protein (aprotinin). Even in case of strict local application, there is
a risk of anaphylactic reactions, linked to the presence of bovine aprotinin. The risk seems
higher in case of previous exposure, even if it was well tolerated. Therefore any use of
aprotinin or aprotinin-containing products should be documented in the patients’ records.

In case of shock, standard medical treatment for shock should be implemented.


CSL Behring
Beriplast P Combi-Set

Special note on local injection:


Administration of Beriplast in the endoscopic treatment of gastrointestinal bleedings can
cause tissue damage, which can lead to formation of intramural haematoma. Abdominal
pain, nausea, or vomiting within 1 to 3 days after such endoscopic treatment can constitute
symptoms of intramural haematoma. In patients with intramural haematoma of the duodenal
wall, pancreatitis has been reported in single literature cases. Therefore, differential
diagnosis for pancreatitis should be carefully evaluated.

Virus safety
Standard measures to prevent infections resulting from the use of medicinal products
prepared from human blood or plasma include selection of donors, screening of individual
donations and plasma pools for specific markers of infections and the inclusion of effective
manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal
products prepared from human blood or plasma are administered, the possibility of
transmitting infective agents cannot be totally excluded. This also applies to unknown or
emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as human
immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV). The
measures taken may be of limited value against non-enveloped viruses such as hepatitis A
virus and parvovirus B19.

Parvovirus B19 infection may be serious for pregnant women (fetal infection) and for
individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).

It is strongly recommended that every time that Beriplast is administered to a patient, the
name and batch number of the product are recorded in order to maintain a link between the
patient and the batch of the product.

4.5 Interaction with other medicinal products and other forms of interaction

No formal interaction studies have been performed. Similar to comparable products or


thrombin solutions, the product may be denatured after exposure with solutions containing
alcohol, iodine or heavy metals (e.g., antiseptic solutions). Such substances should be
removed to the greatest possible extent before applying the product.
CSL Behring
Beriplast P Combi-Set

4.6 Fertility, pregnancy and lactation

Pregnancy and Breastfeeding


The safety of fibrin sealant/haemostatics for use in human pregnancy or breastfeeding has
not been established in controlled clinical trials. Experimental animal studies are insufficient
to assess the safety with respect to reproduction, development of the embryo or foetus, the
course of gestation and peri- and postnatal development.
Only limited experience regarding the administration of Beriplast in pregnant women is
available. Therefore, the product should be administered to pregnant and lactating women
only if clearly indicated.

Fertility
No fertility data are available.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

The following standard categories of frequency are used:


Very common ≥ 1/10
Common ≥ 1/100 and < 1/10
Uncommon ≥ 1/1,000 and < 1/100
Rare ≥ 1/10,000 and < 1/1,000
Very rare < 1/10,000

Gastrointestinal disorders
Administration in the endoscopic treatment of gastrointestinal bleeding can cause tissue
damage, which can lead to formation of intramural haematoma (see section 4.4).

Vascular disorders
Inadvertent intravascular injection could lead to thromboembolic event and DIC, and there
is also a risk of anaphylactic reaction (see section 4.4).

Immune system disorders


Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging
at the application site, bronchospasm, chills, flushing, generalised urticaria, headache, hives,
hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling,
vomiting, wheezing) may occur in rare cases in patients treated with fibrin
sealants/haemostatics. In isolated cases, these reactions have progressed to severe
anaphylaxis. Such reactions may especially be seen, if the preparation is applied repeatedly,
or administered to patients known to be hypersensitive to aprotinin (see section 4.4) or other
constituents of the product.
Antibodies against components of fibrin sealant/haemostatic products may occur rarely.
CSL Behring
Beriplast P Combi-Set

For safety information with respect to transmissible agents see section 4.4.

Reporting of suspected adverse reactions


Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions via the
national reporting system listed in Appendix V.

4.9 Overdose

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Local hemostatics, ATC code: B02BC

The fibrin adhesion system initiates the last phase of physiological blood coagulation.
Conversion of fibrinogen into fibrin occurs by the splitting of fibrinogen into fibrin
monomers and fibrinopeptides. The fibrin monomers aggregate and form a fibrin clot.
Factor XIIIa, which is activated from factor XIII by thrombin, crosslinks fibrin. Calcium
ions are required for both, the conversion of fibrinogen and the crosslinkage of fibrin.
As wound healing progresses, increased fibrinolytic activity is induced by plasmin and
decomposition of fibrin to fibrin degradation products is initiated.

5.2 Pharmacokinetic properties

Beriplast is intended for epilesional use only. Intravascular administration is


contraindicated. As a consequence, intravascular pharmacokinetic studies were not
performed in man.

Fibrin sealants/haemostatics are metabolized in the same way as is endogenous fibrin by


fibrinolysis and phagocytosis.
Beriplast is only applied locally and thus immediately available.

5.3 Preclinical safety data

Single dose toxicity data reveal no special hazard for humans, beyond the information
included in other parts of the SPC. Due to its nature as well as its special method of
application no genotoxicity and cancerogenicity studies have been performed.
CSL Behring
Beriplast P Combi-Set

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Combi-Set I
Vial 1: powder
human albumin, L-arginine hydrochloride, L-isoleucine, sodium chloride, sodium
citrate dihydrate, sodium L-glutamate monohydrate
Vial 2: solvent
sodium chloride, water for injections
Combi-Set II
Vial 3: powder
sodium chloride, sodium citrate-dihydrate
Vial 4: solvent
water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those
mentioned in section 6.6.

6.3 Shelf life

2 years

Chemical and physical in-use stability has been demonstrated for 24 hours at room
temperature (up to max. +25 °C). However, from a microbiological point of view, unless the
method of reconstitution precludes the risk of microbial contamination, the product should
be used immediately.

6.4 Special precautions for storage

Store in a refrigerator (2 °C - 8 °C). Do not freeze. Keep the container in the outer carton in
order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
CSL Behring
Beriplast P Combi-Set

6.5 Nature and contents of container

Immediate containers
Injection vials:
Colourless glass,
- Type I acc. to Ph. Eur. in case of Fibrinogen Concentrate 0.5 and 1 ml, Aprotinin
Solution, Thrombin and Calcium Chloride Solution
- Type II acc. to Ph. Eur. in case of Fibrinogen Concentrate 3 ml each sealed with rubber
stopper and aluminium cap.

Presentations
Pack for Beriplast P 0.5 ml
Combi-Set I for preparing the fibrinogen solution, consisting of vials 1 and 2 linked together
via a transfer device:
 Vial 1 containing powder of fibrinogen and coagulation factor XIII
 Vial 2 containing aprotinin solution
Combi-Set II for preparing the thrombin solution, consisting of vials 3 and 4 linked together
via a transfer device:
 Vial 3 containing thrombin powder
 Vial 4 containing calcium chloride solution
Application set, consisting of:
 2 sterile disposable tuberculin syringes
 Pantaject application kit
 2 sterile disposable spray-tips
 4 sterile disposable cannulas

Pack for Beriplast P 1 ml


Combi-Set I for preparing the fibrinogen solution, consisting of vials 1 and 2 linked together
via a transfer device:
 Vial 1 containing powder of fibrinogen and coagulation factor XIII
 Vial 2 containing aprotinin solution
Combi-Set II for preparing the thrombin solution, consisting of vials 3 and 4 linked together
via a transfer device:
 Vial 3 containing thrombin powder
 Vial 4 containing calcium chloride solution
Application set, consisting of:
 2 sterile disposable tuberculin syringes
 Pantaject application kit
 2 sterile disposable spray-tips
 4 sterile disposable cannulas
CSL Behring
Beriplast P Combi-Set

Pack for Beriplast P 3 ml


Combi-Set I for preparing the fibrinogen solution, consisting of vials 1 and 2 linked together
via a transfer device:
 Vial 1 containing powder of fibrinogen and coagulation factor XIII
 Vial 2 containing aprotinin solution
Combi-Set II for preparing the thrombin solution, consisting of vials 3 and 4 linked together
via a transfer device:
 Vial 3 containing thrombin powder
 Vial 4 containing calcium chloride solution
Application set, consisting of:
 2 sterile disposable 3 ml syringes
 Pantaject application kit
 3 sterile disposable spray-tips
 4 sterile disposable cannulas

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Beriplast must not be used after the expiry date given on the pack and container.
The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or
have deposits. Reconstituted solutions should be inspected visually for particulate matter
and discoloration prior to administration.

Preparation and withdrawal of the solutions


(see Figures 1 to 4 in the lid of the outer carton):
– Before reconstitution bring all Beriplast components to room temperature (not exceeding
+25 °C).
– Take the cardboard stand (containing Combi-Sets I and II) out of the outer carton and
place in a vertical position.
– Do not open the sterile blister packaging and leave the Combi-Sets I and II in the
cardboard stand.
– Reconstitute each set separately.
– Apply strong pressure to the top of the upright Combi-Sets in order to transfer the
solvents from the solvent vial (2 resp. 4) into the vial with the powder (1 resp. 3).
– The solvent is drawn in by vacuum via the transfer device (see Fig. 1).
– Afterwards leave to stand at room temperature. The process of reconstitution is complete
after five to ten minutes at the latest. A clear to slightly opalescent solution is obtained.
Air-bubbles may make the viscous solution appear turbid but such turbidity does not
interfere with the efficacy or usability of the product.
– Note the date and time of reconstitution in the empty space on the cardboard stand (space
on right side).
– Ensure that Combi-Sets I and II are stored in an upright position once reconstituted.
– Prior to use tear open the sterile blister packaging (see Fig. 2) and remove Combi-Set I
and II under sterile conditions. Disconnect the empty vials (2 resp. 4) plus transfer
devices (see Fig. 3).
CSL Behring
Beriplast P Combi-Set

– Incline Vial 1 (fibrinogen solution/blue marking) and draw up the contents into the blue
marked syringe. Completely draw up the contents of Vial 3 (thrombin solution/red
marking) into the red marked syringe (see Fig. 4).

Use the reconstituted solutions immediately after withdrawal into the syringes.
Any unused medicinal product or waste material should be disposed of in accordance with
local requirements.

Application
Prior to applying Beriplast the surface area of the wound needs to be dried by standard
techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

Separate application of fibrinogen solution and thrombin solution:


a) Apply the fibrinogen solution to the tissue site requiring adhesion and immediately
overlay with the thrombin-containing solution.
b) The tissues requiring adhesion should be fixed in place for several minutes until
provisional adhesion is achieved.

Joint application with Pantaject application kit:


For joint application of fibrinogen solution and thrombin solution, the application kit can be
used.

Handling of the application kit for Beriplast (see diagram on the application kit):
Remove the needles from the syringes filled with the fibrinogen solution (blue marking) and
thrombin solution (red marking).
(A) Insert the Y-piece (3) in the conical recess of the syringe holder (4).
(B) Firmly connect to the Y-piece (3) the syringes filled with the fibrinogen solution
(1/blue marking) and thrombin solution (2/red marking).
(C) Snap both syringes into the syringe holder (4).
(D) Connect the grip plate (5) to the syringe plungers to prevent jamming of the syringe
plungers and to ensure smooth forward movement.
(E) Finally firmly screw on the spray tip (6) or the application cannula (7) (both equipped
with a Luer-Lock connector).

For covering large wound surfaces the fibrin sealant can be sprayed using the enclosed
spray-tips, or used in combination with fleece consisting of e.g. polyglycolic acid or
collagen.
Before use in the wound region the system must be checked for blockages. Never push the
syringe plungers against a resistance! Any interruption in the application, even of short
duration, results in blockage of both either the spray tip or application cannula. In such cases
the spray tip or application cannula is unsuitable for further use and must be replaced. For
this purpose the 0.5 and 1 ml Beriplast packages contain two spray tips and the 3 ml
packages contain three spray tips; each package contains four blunt application cannulas.
By applying an even pressure to the grip plate – like for an injection – the fibrin sealant is
sprayed from the spray tip as a fine, even aerosol. The best distance is about 10 cm. A fine
film of fibrin sealant forms on the tissue to be coated.
CSL Behring
Beriplast P Combi-Set

7. MARKETING AUTHORISATION HOLDER

CSL Behring GmbH


Emil-von-Behring-Str. 76
35041 Marburg
Germany

8. MARKETING AUTHORISATION NUMBER

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

April 2013